This is a revised competing renewal application for a program project grant (PPG) that focuses on subcortical ischemia vascular dementia (SIVD) in comparison to Alzheimer disease (AD). Based upon new findings during the initial funding period, we propose that dementia in both AD and SIVD is associated with changes in cerebral cortex, including atrophy, glucose hypometabolism, and loss of N-acetylaspartate [NAA]. The mechanisms leading to these cortical changes, however, are likely to differ and during the renewal we will further explore the mechanisms operant in SIVD. Using a longitudinal study design, we will also determine whether the regional pattern or rate of structural, metabolic, biochemical and perfusion changes are helpful for differential diagnosis and prognosis. The Central Coordinating Core (CC) will continue to recruit and follow to autopsy 500 subjects representing a spectrum of cognitive impairment, as well as ischemic vascular- and AD- type pathology. The Imaging Core will localize lacunes and measure volumes of lacunes (L), white matter lesions (WML), cortical gray matter (cGM)), and hippocampus (HV). The Pathology Core will determine the nature and rate the severity of neurodegenerative, ischemic, and cerebrovascular lesions. Four research projects are proposed (Note: Project 4 was discontinued): Project 1 (Reed et al.) Will used fluoro deoxyglucose positron emission tomography (FDG-PET) to study the utility of the regional and longitudinal pattern of cerebral metabolic rate for glucose (CMRgic) for differential diagnosis and prognosis. Project 2 (Weiner et al.) will use 1H MRSI and perfusion MR to study the utility of [NAA], myoinositol, and blood flow for diagnosis and prognosis. Project 3 (Chui et al) will co-register the clinical MRI to post-mortem brain to determine the pathological correlates of hippocampal and cortical atrophy, WML, and lacunes. Project 5 (Mungas et al) will use multi- variate random effect analyses to model, over time, the neuropsychological and MRI measures correlates of dementia in SIVD and AD. By integration of multi-dimensional data obtained using state of the art methods, we propose to advance understanding of the pathogenesis of SIVD, and to provide practical tools for diagnosis and prognosis.